Obstructive sleep apnea treatment devices, systems and methods

ABSTRACT

Devices, systems and methods of neurostimulation for treating obstructive sleep apnea.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 12/980,840, filed Dec. 29, 2010, which is a continuation ofU.S. patent application Ser. No. 12/650,045, filed Dec. 30, 2009, whichclaims the benefits of priority to U.S. Provisional Patent ApplicationNo. 61/204,008, filed on Dec. 31, 2008. This patent application is alsorelated to U.S. patent application Ser. Nos. 11/907,532 and 11/907,533,both filed on Oct. 12, 2007, corresponding to U.S. Patent ApplicationPublication Nos. 2008/0103407 and 2008/0103545, respectively. The entirecontents of each of these applications is incorporated herein byreference.

FIELD OF THE INVENTION

The inventions described herein relate to devices, systems andassociated methods for treating sleep disordered breathing. Moreparticularly, the inventions described herein relate to devices, systemsand methods for treating obstructive sleep apnea.

BACKGROUND OF THE INVENTION

Obstructive sleep apnea (OSA) is highly prevalent, affecting one in fiveadults in the United States. One in fifteen adults has moderate tosevere OSA requiring treatment. Untreated OSA results in reduced qualityof life measures and increased risk of disease including hypertension,stroke, heart disease, etc.

Continuous positive airway pressure (CPAP) is a standard treatment forOSA. While CPAP is non-invasive and highly effective, it is not welltolerated by patients. Patient compliance for CPAP is often reported tobe between 40% and 60%.

Surgical treatment options for OSA are available too. However, they tendto be highly invasive (result in structural changes), irreversible, andhave poor and/or inconsistent efficacy. Even the more effective surgicalprocedures are undesirable because they usually require multipleinvasive and irreversible operations, they may alter a patient'sappearance (e.g., maxillo-mandibular advancement), and/or they may besocially stigmatic (e.g., tracheostomy).

U.S. Pat. No. 4,830,008 to Meer proposes hypoglossal nerve stimulationas an alternative treatment for OSA. An example of an implantedhypoglossal nerve stimulator for OSA treatment is the Inspire™technology developed by Medtronic, Inc. (Fridely, Minn.). The Inspiredevice is not FDA approved and is not for commercial sale. The Inspiredevice includes an implanted neurostimulator, an implanted nerve cuffelectrode connected to the neurostimulator by a lead, and an implantedintra-thoracic pressure sensor for respiratory feedback and stimulustrigger. The Inspire device was shown to be efficacious (approximately75% response rate as defined by a 50% or more reduction in RDI and apost RDI of ≤20) in an eight patient human clinical study, the resultsof which were published by Schwartz et al. and Eisele et al. However,both authors reported that only three of eight patients remained freefrom device malfunction, thus demonstrating the need for improvements.

SUMMARY OF THE INVENTION

To address this and other unmet needs, the present invention provides,in exemplary non-limiting embodiments, devices, systems and methods fornerve stimulation for OSA therapy as described in the following detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary. Together with the following detaileddescription, the drawings illustrate exemplary embodiments and serve toexplain certain principles. In the drawings:

FIG. 1 is a schematic illustration of a system according to anembodiment of the present invention, including internal (chronicallyimplanted) and external components;

FIG. 2 is a perspective view of a stimulation lead for use in the systemshown in FIG. 1, including a detailed view of the distal end of thestimulation lead;

FIG. 3A is a detailed perspective view of the cuff of the stimulationlead shown in FIG. 2;

FIG. 3B is a lateral cross-sectional view of the cuff shown in FIGS. 2and 3A;

FIG. 4A is a perspective view of a respiration sensing lead for use inthe system shown in FIG. 1;

FIG. 4B is a detailed perspective view of the proximal electrode pair ofthe respiration sensing lead shown in FIG. 4A;

FIG. 4C is a perspective view of an alternative respiration sensing leadfor use in the system shown in FIG. 1;

FIG. 5A shows front, side and top views of an implantableneurostimulator for use in the system shown in FIG. 1;

FIG. 5B is a schematic block diagram of electronic circuitry for use inthe implantable neurostimulator shown in FIG. 5A;

FIGS. 6A, 6B, 6C and 6D illustrate a bio-impedance signal, thecorresponding physiological events, and trigger algorithms for use inthe system shown in FIG. 1;

FIG. 7A is a schematic illustration of the programmer system for use inthe system shown in FIG. 1;

FIGS. 7B and 7C are schematic block diagrams of electronic circuitry foruse in the programmer system for shown in FIG. 7A;

FIG. 8A is a schematic illustration of the therapy controller for use inthe system shown in FIG. 1;

FIG. 8B is a schematic block diagram of electronic circuitry for use inthe therapy controller shown in FIG. 8A;

FIG. 9 is a top view of a magnet for use in the system shown in FIG. 1;

FIG. 10A is a schematic illustration of an interface of the system shownin FIG. 1 and polysomnographic equipment as may be used in a sleep studyfor therapy titration or therapy assessment, for example;

FIG. 10B is a schematic illustration of an alternative interface of thesystem shown in FIG. 1;

FIGS. 11A and 11D are anatomical illustrations showing the incisionsites and tunneling paths that may be used for implanting the internalcomponents shown in FIG. 1;

FIG. 11B is a perspective view of a disassembled tunneling tool for usein tunneling the leads of the system shown in FIG. 1;

FIG. 11C is a detailed perspective view of the assembled tunneling toolshown in FIG. 11B, but with the cap removed to expose the jaws forgrasping the lead carrier disposed on the proximal end of a lead;

FIGS. 11E and 11F illustrate an alternative tunneling tool for use intunneling the leads of the system shown in FIG. 1;

FIG. 12 is a schematic illustration of an external stimulator system andpolysomnographic equipment as may be used for direct muscle stimulationusing fine wire electrodes as a therapy efficacy screening method, forexample;

FIG. 13 is a schematic illustration of a bio-impedance monitoring systemusing surface electrodes and polysomnographic equipment as may be usedas a respiratory sensing screening method, for example;

FIGS. 14A and 14B are charts showing various stimulation output modes ofthe implantable neurostimulator shown in FIG. 1 as may be used fortherapy titration, for example; and

FIGS. 15A, 15B, 15C, 16A, 16B, 17, 18A and 18B are charts illustratingvarious therapy titration methodologies.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The following detailed description should be read with reference to thedrawings in which similar elements in different drawings are numberedthe same. The drawings, which are not necessarily to scale, depictillustrative embodiments and are not intended to limit the scope of theinvention.

Overall System

FIG. 1 schematically illustrates a hypoglossal nerve stimulation (HGNS)system 100 comprising internal components 1000 and external components2000. The HGNS system 100 treats obstructive sleep apnea (OSA) byrestoring neuromuscular activity to the genioglossus muscle viastimulation of the hypoglossal nerve (HGN) synchronous with inspirationto mitigate upper airway collapse during sleep. Stimulation is generatedby an implantable neurostimulator (INS) 1100, synchronized withinspiration as measured by respiration sensing leads (RSLs) 1200 usingbio-impedance, and delivered to the hypoglossal nerve by a stimulationlead (STL) 1300. A programmer system 2100 and a therapy controller 2500are wirelessly linked to the INS 1100. The programmer system 2100includes a computer 2300, a programmer interface 2400, and a programmerhead 2200. The programmer system 2100 is used by the physician tocontrol and program the INS 1100 during surgery and therapy titration,and the therapy controller 2500 is used by the patient to controllimited aspects of therapy delivery.

The implanted components 1000 of the HGNS system 100 include the INS1100, STL 1300, and RSLs 1200. The INS is designed to accommodate one ortwo STLs 1300 and one or two RSLs 1200. One STL 1300 may be used forunilateral implantation and unilateral hypoglossal nerve stimulation.Two STLs 1300 may be used for bilateral implantation on both the rightand left hypoglossal nerves to enhance the effects of stimulation.Alternatively, a second STL 1300 may be used as a back-up in the eventof re-operation necessitated by failure or suboptimal placement of thefirst STL 1300. Similarly, one RSL 1200 may be used for respirationdetection, but two RSLs 1200 may be used for enhanced sensing capabilityor redundancy. Alternatively, a second RSL 1200 may be used as a back-upin the event of re-operation necessitated by failure or suboptimalplacement of the first RSL 1200. Port plugs (not shown) may be used toseal the unused ports in the header of the INS 1100. If only one STL1300 and one RSL 1200 are to be used, the INS 1100 may be simplified toaccommodate one of each lead, thus reducing the size and complexity ofthe INS 1100, as well as increasing battery longevity. For purposes ofillustration, not limitation, the INS 1100 is shown with two RSLs 1200and one STL 1300.

The implanted components 1000 may be surgically implanted with thepatient under general anesthesia. The INS 1100 may be implanted in asubcutaneous pocket inferior to the clavicle over the pectoralis fascia.The distal end of the STL 1300 (cuff 1350) may be implanted on thehypoglossal nerve or a branch of the hypoglossal nerve in thesubmandibular region, and the proximal end of the STL 1300 may betunneled under the skin to the INS 1100. The RSL 1300 may be tunneledunder the skin from the INS 1100 to the rib cage. The INS 1100 detectsrespiration via the RSLs 1200 using bio-impedance.

Stimulation Lead (STL)

FIG. 2 schematically illustrates the STL 1300 in more detail. The STL1300 is designed to deliver the stimulation signal from the INS 1100 tothe hypoglossal nerve and includes a proximal connector assembly 1310, amain tubular body 1330, and a distal cuff 1350. The main tubular body ofthe STL includes a sigmoid shaped section 1370 and a distal flexibletransition section 1380 proximal of the cuff. The STL may have a nominaloutside diameter of 0.062 inches to have minimal cosmetic impact, and anoverall length of 17.7 inches (45 cm) (including cuff) to extend fromthe infraclavicular region (INS) to the submandibular region(hypoglossal nerve) and to accommodate anatomical variation.

The main tubular body 1330 of the STL 1300 is designed to withstandgross neck movement as well as mandibular movement and hypoglossal nervemovement caused by talking, chewing, swallowing, etc. To survive in thishigh fatigue environment, the main tubular body 1330 incorporates ahighly compliant silicone jacket in the form of a sigmoid, and twoconductors 1390 (one for cathode electrodes, one for anode electrodes)each comprising ETFE insulated MP35N multifilament cable disposed insidethe jacket in the form of a bi-filar coil (not visible). This designprovides high fatigue resistance and three-dimensional flexibility(bending and elongation).

The proximal connector assembly 1310 is designed to provide a reliablemechanical and electrical connection of the STL 1300 to the INS 1100. Ithas a number of strain relief elements that enable it to withstandhandling during insertion and removal from the INS 1100, as well asadverse conditions encountered when implanted. The connector assembly1310 includes two in-line stainless steel ring contacts (one for eachconductor 1390) and two silicone ring seals. Set screws in the header ofthe INS 1100 bear down on the contacts, and together with the ringseals, provide a sealed mechanical and electrical connection to the INS1100. More detailed views of the cuff 1350 are shown in FIGS. 3A and 3B,wherein FIG. 3A schematically illustrates the cuff 1350 in isometricview, and FIG. 3B schematically illustrates the cuff 1350 incross-sectional view. The cuff 1350 has a hinged oval-shaped siliconebody (collectively 1352 and 1354) to define an oval lumen 1355 thatprovides secure and gentle retention around the hypoglossal nerve. Thecuff 1350 may be designed to fit the nerve very closely to minimizetissue growth between the electrode and nerve. Thus, the cuff may beavailable in two sizes to accommodate nerves of different diameter: asmall size to accommodate nerves having a diameter of up to about2.5-3.0 mm, and a large size to accommodate nerves having a diameter ofup to 3.2-4.0 mm. At 3.0 mm nerve diameter, either size cuff will fitthe nerve with minimal open space for tissue in-growth. Using a largecuff on a 2.5 mm nerve allows clearance between the nerve and electrodewhich promotes capsule formation. This may cause an increase in capturethreshold but will not affect safety. Conversely, a small cuff placed ona large nerve minimizes electrode coverage around the nerve and may falloff with swelling. The short side 1352 (e.g., 4.0 mm long) of the cuffbody fits between nerve branches and connective tissue on the deep sideof the nerve, thereby minimization nerve dissection. The long side 1354(e.g., 10.0 mm long) of the cuff body rests on the superficial side ofthe nerve (where few braches exist) and is connected to the transitionsection 1380 of the main lead body 1330.

A silicone strap 1356 is connected to and extends from the short side1352 of the cuff body. A silicone top plate comprising an integral baseportion 1359 and loop 1358 is attached to and covers the exteriorsurface of the long side 1354 of the cuff body. The strap 1356 freelyslides through the loop 1358, and wraps around the long side 1354 of thecuff body. The strap 1356 is removed from the loop 1358 for placement ofthe cuff 1350 around the nerve and reinserted into the loop 1358 to holdthe cuff 1350 on the nerve. A mark may be disposed on the strap 1356 ofthe small size cuff to indicate that the cuff is too small and that alarger size cuff should be used if the mark does not pass through theloop 1358. The cuff body readily expands along a hinge line 1353(defined at the junction of the short side 1352 to the long side 1354)as well as other portions of the cuff 1350 structure. Expansion of thecuff body accommodates nerves of different diameters and nerve swellingafter implantation, while the strap 1356 remains in the loop 1358 toretain the cuff 1350 on the nerve. In the event of excess nerve swelling(e.g., >50% increase in nerve diameter) or traction from the lead 1300(e.g., as may accidentally occur during implantation), the strap 1356pulls out of the loop 1358 and releases the cuff 1350 from the nerve tominimize the potential for nerve damage.

The cuff body carries four platinum-iridium electrodes 1360 (e.g., 2.0mm² exposed area each for small cuff, 3.0 mm² exposed area each forlarge cuff), with one cathode electrode 1360 on the short side 1352,another cathode electrode 1360 (not visible) diametrically opposed onthe long side 1354, and two anode electrodes 1360 guarding the cathodeelectrode 1360 on the long side 1354. This guarded dual cathodearrangement provides a more uniform electrical field throughout thecross-section of the nerve while minimizing electrical field outside ofthe cuff. One conductor 1390 may be connected to the cathode electrode1360 on the long side, to which the other cathode electrode 1360 on theshort side is connected by a jumper wire. Similarly, the other conductor1390 may be connected to the distal anode electrode 1360, to which theproximal anode electrode 1360 is connected by jumper wire. With thisarrangement, the cathode electrodes are commonly connected to oneconductor 1390 and the anode electrodes are commonly connected to theother conductor 1390.

With the exception of the metal electrode contacts in the cuff, allexternal surfaces of the STL 1300 exposed to the body when implanted maycomprise implantable grade polymers selected from the following:silicone, and fully cured silicone adhesive. The metal electrodecontacts in the cuff may comprise implantable grade platinum-iridium andare secured to the silicone cuff body with silicone adhesive, forexample.

Respiration Sensing Lead (RSL)

FIGS. 4A and 4B schematically illustrate the respiration sensing lead1200 in more detail. The respiration sensing lead 1200 is designed tomeasure bio-impedance and includes a proximal connector assembly 1210, amain tubular body 1220, and two distal ring electrode pairs 1260. Themain tubular body 1220 of the RSL 1200 includes a proximal sigmoidsection 1230 and a distal sigmoid section 1240 between the electrodepairs 1260. The RSL 1200 may have a nominal outside diameter of 0.072inches to have minimal cosmetic impact, and an overall length of 24.3inches (61.6 cm) unstretched, 32.0 inches (81.3 cm) stretched to extendfrom the infraclavicular region (where the INS 1100 is implanted) to theright or left rib cage (where the RSLs 1200 may be implanted) and toaccommodate anatomical variation.

The main tubular lead body 1220 of the RSL 1200 is designed to withstandthoracic movement due to flexion, extension, rotation and breathing. Towithstand this environment, the main tubular body 1220 may include aflexible silicone jacket formed into two sigmoid sections 1230, 1240 andfour conductors comprising small diameter ETFE insulated MP35NLT wires(not visible) disposed inside the jacket in the form of a quad-filarcoil. The proximal sigmoid section 1230 isolates movement of the INS1100 from the electrode pairs 1260 and accommodates anatomic variationsin thoracic length. The distal sigmoid section 1240 allows adjustment inthe distance between electrode pairs 1260 and reduces strain appliedbetween the anchor tabs 1270, which may be secured with sutures to theunderlying fascia when implanted. The proximal sigmoid 1230 section mayhave 3½ wavelengths with a peak-to-peak dimension of approximately 0.94inches (2.4 cm) and an overall length of 5.5 inches (14.0 cm). Thedistal sigmoid 1240 section may have 2½ wavelengths with a peak-to-peakdimension of approximately 0.94 inches (2.4 cm) and an overall length of5.5 inches (14.0 cm).

The two distal electrode pairs 1260 may comprise four electrodes total,and each may comprise MP35N rings having an exposed surface area of 28.0mm², for example. As shown in FIG. 4B, tubular strain relief segments1262 and 1272 may be disposed on the lead body on either side of eachelectrode 1260. Where the strain relief segments 1262 and 1272 areadjacent each other, a gap may be provided there between as shown inFIG. 4B or the segments may abut each other to avoid a stressconcentration point. The anchor tab 1270 may be disposed over anelectrode as shown in FIG. 4B leaving the proximal and distalextremities of the electrode exposed.

At any given time, the INS 1100 detects impedance along a vector, witheach end of the vector defined by one active pair of electrodes 1260. Ineach active pair of electrodes 1260, one electrode delivers a smallexcitation current, and the other electrode monitors the correspondingchange in voltage. The INS 1100 may also act as a current emittingand/or voltage sensing electrode. Changes in impedance are calculated bydividing the change in voltage by the excitation current, whichcorrespond to movement of the diaphragm and lung to produce a signalindicative of respiratory activity.

The proximal connector assembly 1210 of the RSL 1200 is designed toprovide a reliable mechanical and electrical connection of the RSL 1200to the INS 1100. It has a number of strain relief elements that enableit to withstand handling during insertion and removal from the INS 1100,as well as adverse conditions encountered when implanted. The connectorassembly 1210 may include four in-line stainless steel ring contacts(one for each conductor) and four silicone ring seals. Set screws in theheader of the INS 1100 bear down on the contacts, and together with ringseals, provide a sealed mechanical and electrical connection to the INS1100.

With the exception of the distal electrodes, all external surfaces ofthe RSL 1200 exposed to the body when implanted may comprise implantablegrade polymers selected from the following: silicone, and fully curedsilicone adhesive. The distal electrodes may comprise implantable gradeMP35N and are sealed to the lead body with silicone adhesive, forexample.

FIG. 4C schematically illustrates an alternative embodiment of therespiration sensing lead 1200. In this embodiment, the RSL 1200 may havea nominal outside diameter of 0.072 inches to have minimal cosmeticimpact, and an overall length of 23.5 inches (59.7 cm) unstretched, 26.5inches (67.2 cm) stretched. The proximal sigmoid 1230 section may have3½ wavelengths with a peak-to-peak dimension of approximately 0.94inches (2.4 cm) and an overall length of 5.5 inches (14.0 cm). Thedistal sigmoid 1240 section may have ½ wavelength with an amplitude ofapproximately 1.7 inches (4.4 cm) and an overall length of about 0.5inches (1.3 cm).

Implantable Neurostimulator (INS)

FIG. 5A schematically illustrates the INS 1100 in more detail, includinga front view, a top view and a side view. The INS 1100 is similar incertain aspects to commercially available implantable pulse generatorsand implantable neurostimulators, which may be obtained from suitablemanufacturers such as CCC Medical Devices (Montevideo, Uruguay). The INS1100 generally includes a header 1110 for connection of the STL 1300 andRSLs 1200, and a hermetically sealed housing 1120 for containing theassociated electronics 1130 and battery 1140 (e.g., WGL 9086).

The electronic circuitry 1130 contained in the INS 1100 enablestelemetry communication with the programmer system 2100 and therapycontroller 2500, detection of respiration via the RSLs 1200,determination of the trigger point for stimulation, and delivery of acontrolled electrical stimulation signal (pulse train) via the STL 1300.The INS 1100 also records therapy data (device settings, respirationdata, stimulation delivery data, etc.).

The header 1110 may comprise epoxy that is hermetically sealed to thehousing 1120. The housing 1120 may comprise titanium. As mentioned inthe context of respiration sensing, the housing 1120 may be used as anelectrode for bio-impedance respiration measurement. For example, thehousing 1120 may comprise a combination current emitting and voltagesensing electrode for respiration detection.

The header 1110 includes four ports: two RSL ports 1112 (labeled “sense”A and B) for receiving the proximal connectors of up to two RSLs 1200and two STL ports 1114 (labeled “stim” 1 and 2) for receiving theproximal connectors of up to two STLs 1300. Each port that is configuredto receive a STL 1300 includes two set screws (labeled “−” for cathodeand “+” for anode) with associated set screw blocks and seals formechanical and electrical connection to corresponding contacts on theproximal connector 1310 of the STL 1300. Similarly, each port that isconfigured to receive a RSL 1200 includes four set screws (two labeled“I” for current emitting electrodes and two labeled “V” for voltagesensing electrodes) with associated set screw blocks and seals formechanical and electrical connection to corresponding contacts on theproximal connector 1210 of the RSL 1200. The header 1110 furtherincludes two suture holes 1116 (only one is visible) for securing theINS 1100 to subcutaneous tissue such as muscle fascia using sutures whenimplanted in a subcutaneous pocket. As shown, approximate dimensions,component values and component configurations are given by way ofexample, not limitation.

The INS 1100 generates the stimulation output for delivery to thehypoglossal nerve by way of the STL 1300. For this purpose, the INS 1100has two bipolar stimulation output channels, one channel correspondingto each STL port 1114, with each channel providing a pulse train ofconstant current with a frequency range of 20 to 50 Hz, a pulse widthrange of 30 to 215 μs, an amplitude range of 0.4 to 5.0 mA, and astimulation duty cycle range of 41%-69%, by way of example, notlimitation.

The INS 110 also generates the excitation signal and measures voltage byway of the RSLs 1200 for bio-impedance respiration detection. For thispurpose, the INS 1100 also has two respiration sensing channels, onechannel corresponding to each RSL port 1112, with each channel providinga small excitation current (“I”) and measuring voltage (“V”). Theexcitation signal may comprise a 10 Hz biphasic constant current pulse,with the positive and negative phases of each biphasic pulse having anamplitude of 300 μA, a duration of 50 μs, and a charge of 15 nC. Changesin impedance (“Z”) are calculated by dividing the change in measuredvoltage (“V”) by the excitation current (“I”), which corresponds tomovement of the diaphragm, lung, and other structures to produce asignal indicative of respiratory activity.

With reference to FIG. 5B, a block diagram of an example of the INScircuit 1130 is shown schematically. The INS circuit 1130 utilizes amicroprocessor to control telemetry communications with the programmersystem 2100, operating the sensing circuits to monitor respiration viathe RSLs 1200, controlling the delivery of output stimuli via the STLs1300, monitoring the magnetically sensitive reed switch and thereal-time clock. The microprocessor contains built-in support circuits(RAM, Flash Memory, Analog to Digital (A/D) Converter, Timers, SerialPorts and Digital IO) used to interface with the rest of the INS circuit1130. The microprocessors. Two microprocessors communicating via aserial link may be used instead of one microprocessor, with the firstmicroprocessor for telemetry communications, monitoring the magneticallysensitive reed switch and the real-time clock; and the secondmicroprocessor for operating the sensing circuits and controlling thedelivery of output stimuli.

The telemetry interface circuits consist of a tuned telemetry coilcircuit and a telemetry driver/receiver circuit to allow pulse encodedcommunication between the external programmer system 2100 and themicroprocessor. As an alternative to telemetry coils and an inductivelink, RF antennae with associated circuitry may be used to establish aRF link to provide for arms-length telemetry. The reed switch provides ameans for the INS 1100 to be controlled by using a magnet placed inclose proximity thereto. The real-time clock provides the basic timebase (32 KHz) for the INS circuit 1130 as well as a clock (year, day,hour, minute, second) which can be used to control the scheduleddelivery of therapy. The clock is also used to time-stamp informationabout the operation of the system that is recorded on a nightly basis.

The respiratory sensing circuits comprise two main parts: the excitationcurrent source (output) and the voltage sensing circuit (input). As willbe described in more detail hereinafter, respiration is detected via theRSLs 1200 using a 4-wire impedance measurement circuit, where anexcitation current is driven through a pair of electrodes, and theresulting voltage is measured on a separate pair of electrodes.Electrode switching circuits (one for each RSL 1200) allows the INS 1100to monitor one of several different vectors from the two separate 4electrode RSLs 1200. The INS housing 1120 may also be used as both anexcitation and sensing electrode. The excitation current circuitdelivers biphasic pulses of low level (300 uA) current to the selectedelectrode pair every 100 ms during sensing. The voltage sensingamplifier circuit synchronously monitors the voltage produced by theexcitation current on the selected electrode pair. The resulting outputsignal is proportional to the respiratory impedance (0.2Ω to 10Ω) and isapplied to the A/D circuit in the microprocessor for digitization andanalysis.

The stimulation output circuits deliver bursts of biphasic stimulationpulses to either STL 1300. These bursts may be synchronized to thesensed respiratory waveform. The stimulation output circuits include anelectrode switching network, a current source circuit, and an outputpower supply. The electrode switching network allows selection of thestimulation output channel (pair A or B), each corresponding to a STL1300. The electrode switching network also allows for a charge balancingcycle following each stimulation pulse during which the outputs areconnected together with no applied output pulse. The timing and polarityof the pulse delivery is provided by control outputs of themicroprocessor. The microprocessor selects the amplitude (e.g., 0.5 mAto 5 mA) of the output current from the current source circuit which isapplied through the switching network. The output power supply convertsbattery voltage to a higher voltage (e.g., 5V to 13V) which issufficient to provide the selected current into the load impedance ofthe STL 1300. The microprocessor measures the voltage output from theelectrode switching network resulting from the delivered current and theload impedance. The microprocessor divides the output voltage by theoutput current resulting in a measure of the load impedance (600Ω to2500Ω) which can be an indicator of integrity of the STL 1300.

With reference to FIG. 6A, the bio-impedance respiration signal (“Z”),which is generated by dividing the change in measured voltage (“V”) bythe excitation current (“I”), tracks with diaphragm movement (DM) overtime and therefore is a good measure of respiratory activity, and may beused to measure respiratory effort, respiratory rate, respiratory(tidal) volume, minute volume, etc. If the excitation current (I) isconstant or assumed constant, then the bio-impedance (Z) is proportionalto the measured voltage (V), and thus the voltage (V) may be used as asurrogate for bio-impedance (Z), thereby eliminating the division step.As used in this context, diaphragm movement includes movements and shapechanges of the diaphragm and adjacent tissue that occur during normalbreathing and during obstructed breathing. The (positive or negative)peak (P) of the impedance signal (Z) corresponds to the end of theinspiratory phase and the beginning of the expiratory phase. If thesignal is normal (as shown), the positive peak is used; and if thesignal is inverted, the negative peak is used. The beginning of theinspiratory phase occurs somewhere between the peaks and may not bereadily discernable. Thus, the impedance signal provides a reliablefiducial (P) for end-inspiration and begin-expiration (also calledexpiratory onset), but may not provide a readily discernable fiducialfor begin-inspiration (also called inspiratory onset). Therefore,algorithms described herein do not rely on begin-inspiration (orinspiratory onset) for triggering stimulation as proposed in the priorart, but rather use a more readily discernable fiducial (P)corresponding to begin-expiration (or expiratory onset) in a predictivealgorithm as described below. Other non-predictive (e.g., triggered)algorithms are described elsewhere herein.

In people without OSA, the hypoglossal nerve usually activatesapproximately 300 ms before inspiration and remains active for theentire inspiratory phase. To mimic this natural physiology, it isdesirable to deliver stimulation to the hypoglossal nerve during theinspiratory phase plus a brief pre-inspiratory period of about 300 ms.As mentioned previously, a reliable fiducial for the beginning of theinspiratory phase may not be available from the impedance signal, and areliable fiducial for the pre-inspiratory period may not be availableeither. However, there are reliable fiducials for the beginning of theexpiratory phase (peak P) which may be used to trigger stimulation tocover the inspiratory phase plus a brief pre-inspiratory period.

Accordingly, an algorithm is used to predict respiratory period anddetermine stimulation trigger time. The predictive algorithm iscontained in software and executed by a microprocessor resident in theINS circuitry 1130, thus enabling the INS 1100 to generate stimulationsynchronous with inspiration.

One example of a predictive algorithm is illustrated in FIG. 6B. In thisexample, the stimulation period is centered about a percentage (e.g.,75%) of the predictive respiratory period. The predictive algorithm useshistorical peak data (i.e., begin-expiration data) to predict the timeto the next peak, which is equivalent to the predicted respiratoryperiod. The stimulation period is centered at 75%, for example, of thepredicted respiratory time period. Thus, the stimulation trigger pointis calculated by predicting the time to the next peak, adding 75% ofthat predicted time to the last peak, and subtracting ½ of thestimulation period (trigger time=time of last peak+75% of predicted timeto next peak−½ stimulation period). A phase adjustment parameter (range:−1500 ms to +500 ms, for example) permits the stimulation period to bebiased early or late. A default setting (e.g., −500 ms) of the phaseadjustment parameter moves the stimulation period early relative to theanticipated start of inspiration.

Another example of a predictive algorithm is illustrated in FIG. 6C.This example differs for the example illustrated in FIG. 6B in that thestimulation period is initiated (not centered) at a percentage (e.g.,50%) of the predicted respiratory period. However, the two examples haveessentially equivalent results for a duty cycle of 50%. As in the priorexample, the predictive algorithm uses historical peak data (i.e.,begin-expiration data) to predict the time to the next peak, which isequivalent to the predicted respiratory period. The stimulation periodmay start at 50%, for example, of the predicted time period. Thus, thestimulation trigger point is calculated by predicting the time to thenext peak and adding 50% of that predicted time to the last peak(trigger time=time of last peak+50% of predicted time to next peak). Aphase adjustment parameter (range: −1500 ms to +500 ms, for example)permits the stimulation period to be biased early or late. A defaultsetting (e.g., −500 ms) of the phase adjustment parameter moves thestimulation period early relative to the anticipated start ofinspiration.

A feature common to the predictive algorithms is illustrated in FIG. 6D.This feature provides a sequence of predicted respiratory periods incase the respiration impedance signal (“Z”) is temporarily lost (e.g.,due to change in respiratory effort). Until a subsequent respiratorypeak is detected, stimulation parameters which are based on the measuredrespiratory period (e.g., stimulation period) are unchanged. Thus,stimulation timing remains synchronous to the last detected peak.

The stimulation duty cycle may vary to meet efficacy and safetyrequirements. Generally, the stimulation duty cycle is used to determinethe stimulation period as a percentage of the predicted respiratoryperiod (stimulation period=duty cycle×predicted respiratory period).After a stimulation period is started, stimulation continues until theend of the stimulation period as set by the stimulation duty cycle, oruntil the next actual peak is detected, whichever occurs first. Notethat the result of the algorithm illustrated in FIG. 6B is the same asthe result of the algorithm illustrated in FIG. 6C for a stimulationduty cycle of 50%.

The stimulation duty cycle may be fixed or adaptive. In the fixed mode,the stimulation duty cycle is set using to programmer system 2100 to afixed value. This fixed value may be increased when the respiratorysignal is lost. In adaptive mode, the duty cycle is allowed to vary as afunction of a characteristic of respiration. For example, the adaptiveduty cycle may increase with an increase in respiratory periodvariability or with the loss of respiratory signal. Thus, in someinstances, the stimulation duty cycle may run above normal (e.g., above50% to 60%) to achieve a better likelihood of covering the inspiratoryphase. Because above normal stimulation duty cycle may result in nerveand/or muscle fatigue if prolonged, it may be desirable to offsetabove-normal stimulation periods with below-normal stimulation periodsto result in a net normal duty cycle. For example, if a X % stimulationduty cycle is defined as normal and the adaptive mode results in aperiod T1 where the stimulation duty cycle runs Y % more than X %, theabove-normal stimulation period may be proportionally offset by abelow-normal stimulation period T2 where the stimulation duty cycle runsZ % less than X % to satisfy the equation Y×T1=Z×T2. This equation isapproximate and may vary slightly depending on the averaging techniqueused. Other offset methods may be used as an alternative.

The following stimulation duty cycle parameters are given by way ofexample, not limitation. In fixed mode, the maximum stimulation dutycycle may be set from 41% to 69% in 3% increments, and the defaultsetting may be 50%. In adaptive mode, the stimulation duty cycle for arespiratory period may vary from 31% to 69% in 3% increments, and themaximum running average may be set to 53%. As mentioned above, theadaptive mode allows the duty cycle to increase with respiratory periodvariability, for example, and the stimulation duty cycle may run inexcess of 53% for a limited period of time, but those periods areproportionally offset by periods where the stimulation duty cycle runsless than 53% (e.g., according to an exponentially weighted movingaverage). For example, an adaptive duty cycle set to 69% would run atthat level for no longer than 5 to 7 minutes before being offset by alower stimulation duty cycle at 47% to result in a running average of53%.

Programmer System

As shown schematically in FIG. 7A, the programmer system 2100 includes acomputer 2300, a programmer interface 2400 and a programmer head 2200.The programmer interface 2400 and programmer head 2200 are similar incertain aspects to commercially available programmers, which may beobtained from suitable manufacturers such as CCC Medical Devices(Montevideo, Uruguay). The programmer head 2200 is connected to theprogrammer interface 2400 via a flexible cable 2210, and the programmerinterface 2400 is connected to the computer 2300 via a USB cable 2310.Cable 2210 may be coiled as shown or straight. The programmer system2100 wirelessly communicates with the INS 1100 via a wireless telemetrylink (e.g., 30 KHz) utilizing an antenna and associated circuitry in theprogrammer head 2200. The programmer interface 2400 provides analog todigital conversion and signal processing circuitry allowing the computer2300 to control and program the INS 1100 via the programmer head 2200.The programmer head includes a power indication LED 2220, a signalstrength LED array (signal strength to/from INS 1100), an interrogatebutton 2240 (to download data from INS 1100), a program button 2250 (toupload data/commands to the INS 1100) and a therapy-off button 2260 (tostop therapy/stimulation output from the INS 1100). The computer 2300may comprise a conventional laptop computer with software to facilitateadjustment of a variety of INS 1100 parameters, including, for example:stimulation parameters (stimulation pulse amplitude, stimulation pulsefrequency, stimulation pulse width, stimulation duty cycle, etc.);respiration sensing algorithm parameters; stimulationtrigger/synchronisation algorithm parameters, therapy delivery schedule,and various test functions.

With reference to FIG. 7B, a block diagram of example circuits 2420/2270for the programmer interface 2400 and the programmer head 2200 are shownschematically. The programmer interface circuit 2420 is controlled by amicroprocessor having a standard set of peripherals (RAM, Flash, DigitalI/O, Timers, Serial Ports, A/D converter, etc). The microprocessorcommunicates with a standard personal computer (PC) 2300 through aUniversal Serial Bus (USB) interface. Commands and data are passed fromthe computer 2300 to/from the microprocessor via the USB interface andcable 2310. The USB interface also provides DC power for the programmerinterface circuit 2420 and the programmer head circuit 2270 via cable2210. The microprocessor controls the cable interface leading to theprogrammer head circuit 2270 via cable 2210. The programmer head circuit2270 contains telemetry driver and receiver electronics that interfaceto the telemetry coil. The telemetry coil is designed to inductivelycouple signals from the programmer head circuit 2270 to the coil in theINS circuit 1130 when the programmer head 2200 is placed over the INS110 with the coils aligned. As an alternative to telemetry coils and aninductive link, RF antennae with associated circuitry may be used toestablish a RF link to provide for arms-length telemetry. The programmerhead circuit 2270 also contains electronics that monitor the signalstrength as received from the INS 1100. The outputs of the signalstrength electronics drive display LED's for the user. Another LEDindicates that power is available. The programmer interfacemicroprocessor controls and receives analog input signals from anisolated sensor interface. The power and ground for the sensor interfaceare derived from the USB power input, but provide DC isolation for thiscircuitry to prevent leakage currents from flowing through any patientconnections that may be present at the sensor inputs. The sensor inputsare protected against external high voltages (i.e. defibrillationprotection). The sensor input signals are amplified and filteredappropriately for the sensor type. The amplifier gain and filtercharacteristics may be controlled by microprocessor. The signals to/fromthe amplifier circuit are DC isolated to prevent leakage currents fromflowing through any patient connections that may be present at thesensor inputs. The sensor signals are digitized by the microprocessorand are transmitted through the USB link to the PC along with thetelemetered signals from the INS 1100.

With reference to FIG. 7C, a block diagram of example circuit 2440 forthe marker box 2430 is shown schematically. Generally, marker box 2430and associated circuitry 2440 replace the D/A circuits and analogoutputs 2410 of programmer interface circuit 2420 shown in FIG. 7Bproviding for the alternative arrangement illustrated in FIG. 10B. Themarker box circuit 2440 is separately connected to a Universal SerialBus (USB) port of the programmer computer 2300 via a USB cable. The USBinterface also provides DC power for the marker box circuit 2440 via theUSB cable. The power and ground for the marker box circuit 2440 arederived from the USB power input, but provide DC isolation for thiscircuitry to prevent leakage currents from flowing through any equipmentthat may be connected to the patient. Analog marker output data signalsare transmitted from the PC 2300 to control the digital to analog (D/A)converter outputs. These analog output signals may be connected tostandard PSG recording equipment 2800. Signals from the INS 1100 (suchas sensed respiration impedance and stimulation output amplitude) can berepresented by these outputs to allow simultaneous recording with otherstandard PSG signals (flow, belts, EMG/ECG, etc).

Therapy Controller

As shown schematically in FIG. 8A, the therapy controller 2500 may beused by the patient to control limited aspects of therapy delivery. Thetherapy controller 2500 is similar in certain aspects to commerciallyavailable patient controllers, which may be obtained from suitablemanufacturers such as CCC Medical Devices (Montevideo, Uruguay). Thetherapy controller 2500 houses a battery, an antenna, and associatedcircuitry (not visible) to control limited aspects of therapy deliveryvia a wireless telemetry link (e.g., 30 KHz) with the INS 1100. Therapyis normally set for automatic delivery according to a predefinedschedule (set by physician using the programmer during titration) butmay also be operated in a manual mode. The therapy controller has a userinterface including start button 2510 (to start therapy delivery), astop button 2520 (to stop therapy delivery) and a pause button (to pausetherapy delivery), each with associated LED indicators 2540 which flashwhen the corresponding button is depressed and illuminate steadily whenthe command is received by the INS 1100. The user interface alsoincludes a schedule set LED 2550 that illuminates if a therapy deliveryschedule has been programmed, and a contact physician LED 2560 thatilluminates in the event of a low battery or a malfunction requiring aphysician visit.

With reference to FIG. 8B, a block diagram of an example circuit for thetherapy controller 2500 is shown schematically. The therapy controllercircuit 2570 includes a battery powered microprocessor having a standardset of peripherals (RAM, Flash, Digital I/O, Timers, Serial Ports, A/Dconverter, etc). The microprocessor operates in a low power mode toconserve battery power. The microprocessor controls the telemetry driverand receiver electronics that interface with the telemetry coil. Thetelemetry coil is designed to inductively couple signals to the INStelemetry coil when aligned. The microprocessor monitors the membraneswitches and reacts to switch closures by activating display LED's andinitiating telemetry commands to the INS. After communicating with theINS, status information can be displayed to the user. The microprocessoralso controls a beeper which can provide audio feedback to the user whenbuttons are pressed and to indicate the success or failure ofcommunications with the INS.

Magnet

As schematically shown in FIG. 9, an annular magnet 2600 may be providedto the patient to deactivate the INS 1100 in the event the therapycontroller 2500 is not available or functioning. The magnet 2600 maycomprise a permanent annular-shaped magnet made of ferrite strontiummaterial coated with epoxy. The magnet 2600 may produce a strong fieldof 90 Gauss at 1.5 inches from the surface of the magnet along thecenterline of the hole. The magnet 2600 may be used (or carried by) thepatient in case of emergency. When temporarily (2 seconds or more)placed over the implanted INS 1100 on the skin or clothing, the magnet2600 disables current and future therapy sessions. Although therapysessions are disabled by the magnet 2600, all other functions of the INS1100 may remain enabled including telemetry communication with theprogrammer system 2100 and therapy controller 2500. Therapy sessions maybe re-enabled using the programmer system 2100. The therapy controller2500 may also re-enable therapy sessions if the therapy controller 2500has been authorized by the programmer system 2100 to do so.

Interface with PSG Equipment

The programmer interface 2400 may include an input/output (I/O) link2410 to allow connection to polysomnographic (PSG) equipment 2800 asschematically shown in. FIG. 10A. Typical PSG equipment 2800 includes acomputer 2810 connected to a plurality of sensors (e.g., airflow sensor2820, respiratory effort belts 2830) via interface hardware 2840. TheI/O link 2410 may be used in a number of different ways. For example,analog data signals from the PSG equipment 2800 may be downloaded to thecomputer 2300 of the programmer system 2100 to record and/or display PSGdata (e.g. airflow) together with therapy data. Alternatively or inaddition, digital data signals from the INS 1100 and/or the programmersystem 2100 may be uploaded to the computer 2810 of the PSG equipment2800 to record and/or display therapy data (e.g., stimulation and/orrespiration data) together with PSG data. The circuitry corresponding toI/O link 2410 may be incorporated into the programmer interface 2400 asshown in FIG. 10A, or may be incorporated into a separate marker box2430 as shown in FIG. 10B.

Synchronizing data from the sensors 2820/2830 of the PSG equipment 2800with data from the INS 1100 via the programmer system 2100 may bebeneficial to facilitate therapy titration and efficacy measurement.Although the programmer system 2100 and the PSG equipment 2800 may bedirectly connected by I/O link 2410, transmission delay in each systemmay result in asynchrony. Data synchronization between the systems maybe addressed in a number of different ways. For example, if the delaysin each system are relatively fixed and below an acceptable threshold(e.g., 0.5 to 1.0 second), no synchronization step need be taken. If thedelays in each system are relatively fixed but above an acceptablethreshold (e.g., above 0.5 to 1.0 second), data from the system withless delay may be offset (delayed) by a fixed time value to align withdata from the system with more delay. As an alternative, a timing signal(e.g., from a clock signal generator separate from or integral with oneof the systems) may be input into the PSG equipment 2800 and programmersystem 2100 to allow time stamped data independently collected by eachsystem to be merged and synchronized by post processing.

Treatment Overview

FIG. 11A schematically illustrates the incision sites (solid thicklines) and tunneling paths (dotted lines) for implanting the INS 1100,STL 1300 and RSLs 1200. The implant procedure may be performed by asurgeon (e.g., otolaryngologist) in a 1-2 hour surgical procedure withthe patient under general anesthesia, for example. In general, theimplant procedure involves placing the cuff 1350 of the SU 1300 on thehypoglossal nerve via a submandibular dissection, and tunneling the leadbody 1330 and sigmoid section 1370 of the STL 1300 subcutaneously downthe neck to the INS 1100 in a subcutaneous pocket in the infraclavicularregion. From the infraclavicular pocket, the RSLs 1200 may be tunneledsubcutaneously toward midline and then laterally along the costalmargins.

After a healing period of a few weeks, the patient returns to the sleeplab where a sleep technician, under the supervision of a certified sleepphysician (e.g., pulmonologist), uses the programmer system 2100 toprogram the INS 1100 (e.g., set the therapy delivery schedule andtitrate the stimulus to optimize efficacy during sleep).

Immediately after the titration visit, the patient may return home andbegin use. A therapy delivery session may begin according to thepre-defined therapy delivery schedule, which may be set to coincide withwhen the patient normally goes to sleep. At the beginning of a therapydelivery session, stimulus may be delayed for a period of time to allowthe patient to fall asleep. The therapy delivery session may endaccording to the pre-defined therapy delivery schedule, which may be setto coincide with when the patient normally wakes up. The therapydelivery session may be programmed to not exceed eight hours. Thepatient can use the therapy controller 2500 to adjust limited aspects oftherapy delivery. For example, the patient can use the therapycontroller 2500 to stop, pause and restart a scheduled therapy session.In addition, the therapy controller 2500 can be used to manually controltherapy delivery rather than operate according to a preset schedule.This may be beneficial when the patient has an irregular sleep schedule,for example. In this mode, the therapy controller 2500 can be used bythe patient to manually start, stop, and pause a therapy session.

Surgical Implant Procedure

With continued reference to FIG. 11A, the internal components 1000 maybe implanted using the following surgical procedure, which is given byway of example, not limitation. Unless specifically stated, the order ofthe steps may be altered as deemed appropriate. Although the INS 1100may be surgically implanted on the right or left side, the right side ispreferred to leave the left side available for implantation of cardiacdevices that are traditionally implanted on the left side. The rightside is also preferred for the RSL 1200 (if one RSL is used) to providea clean respiratory signal that is less susceptible to cardiac artifactthan the left side.

Standard surgical instruments may be used for incisions, dissections,and formation of subcutaneous pockets. Commercially available nervedissection instruments may be preferred for dissecting the hypoglossalnerve and placing the STL cuff 1350 on the nerve. A tunneling tool 3000,as schematically shown in FIGS. 11B and 11C, may be used for tunnelingthe STL 1300 and RSL 1200 leads. The tunneling tool (also referred to astunneler) 3000 includes a relatively rigid grasper 3010, a tubularsheath 3020, and a cap 3030. The sheath 3020 and cap 3030 are sized tobe slid over the grasper 3010. The cap 3030 may include a radiopaqueagent such as barium sulfate loaded at 18% by weight, for example. Thegrasper 3010 may be formed of stainless steel and includes a shaft 3012,distal jaws (similar to an alligator clip) 3014, and a proximal handle3016. The jaws 3014 are biased to the closed position and may be used tograsp the proximal end of the RSL 1200 or STL 1300 using the leadcarrier 3100 as protection. The lead carrier 3100 may comprise a smallpolymeric tube with an inside diameter sized to form an interference fitwith the proximal end of the RSL 1200 or STL 1330. The sheath 3020 maycomprise a polymeric tube with two open ends, and the cap 3030 maycomprise a polymeric tube with one open end and one closed end for bluntdissection. The proximal end of the cap 3030 may include a taperedsection to fit into the distal end of the sheath 3020 and form aninterference fit therewith. In the embodiment shown in FIGS. 11B and11C, the sheath 3020 may have an outside diameter of approximately 0.37inches and a length of about 10.9 inches. The cap may an outsidediameter tapering from approximately 0.37 inches and a length of about1.7 inches. The shaft 3012 may have a diameter of about 0.19 inches andtogether with the jaws 3014 may have a length sufficient to fill thelength of the sheath 3020 and cap 3030. The handle 3016 may have adiameter of about 0.5 inches and a length of about 3.0 inches.

An alternative tunneling tool 3000 is schematically shown in FIGS. 11Eand 11F may be used for tunneling the STL 1300 and RSL 1200. In thisembodiment, the tunneling tool 3000 includes a relatively rigid grasper3010, a tubular sheath 3020, and a cap 3030. The sheath 3020 and cap3030 are sized to be slid over the grasper 3010. The cap 3030 mayinclude a radiopaque agent such as barium sulfate loaded at 18% byweight, for example. The grasper 3010 may be formed of stainless steeland includes a shaft 3012, distal connector 3018, and a proximal handle3016. The connector 3018 includes threads that mate with correspondingthreads in the cap 3030. The connector 3018 may also include ring barbsthat form an interference fit with the inside of the lead carrier 3100for releasable connection thereto. The lead carrier 3100 may comprise asmall polymeric tube with an inside diameter sized to form aninterference fit with the proximal end of the RSL 1200 or STL 1330. Thesheath 3020 may comprise a polymeric tube with two open ends, and thecap 3030 may comprise a polymeric tube with one open end and one closedend for blunt dissection. The proximal end of the cap 3030 includesinternal threads to screw onto the connector 3018 and hold the sheath3020 on the shaft 3012. In the embodiment shown in FIGS. 11E and 11F,the sheath 3020 may have an outside diameter of approximately 0.28inches and a length of about 12.3 inches. The cap may an outsidediameter tapering from approximately 0.13 inches and a length of about1.0 inches. The shaft 3012 may have a diameter of about 0.22 inches andmay have a length sufficient to fill the length of the sheath 3020. Thehandle 3016 may have a diameter of about 0.5 inches and a length ofabout 3.74 inches.

The patient is prepared for surgery using conventional practiceincluding standard pre-operative care procedures, administration ofantibiotics as appropriate, and administration of steroids asappropriate to reduce swelling around the nerve dissection. Becausetongue movement must be observed during test stimulation, it isrecommended that no long-acting muscle relaxants be used during surgicalpreparation no muscle relaxants be used during implant. Generalanesthesia is administered according to conventional practice and thepatient is intubated using an endotracheal tube, taking care to positionthe endotracheal tube so that the tongue is free to protrude during teststimulation.

The neck is then extended to expose right submandibular region and asterile field is created around the neck and thorax, taking care toavoid obstructing visualization of the oral cavity (a clear steriledrape over the mouth may be used). By way of a neck incision (A), thehypoglossal nerve is then exposed deep to the submandibular gland.Because the INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing, this dissection isalso preferably performed on the right side. The branch of thehypoglossal nerve believed to innervate the genioglossus muscle is thenidentified and isolated. Confirmation of correct nerve location may beachieved by performing a test stimulation later in the procedure. Theidentified nerve branch is then circumferentially dissected toaccommodate the cuff 1350. The short side 1352 of the cuff 1350 isdesigned to reside on the deep side of the nerve, and the long side 1354of the cuff 1350 is designed to reside on the superficial side of thenerve.

The appropriate sized cuff 1350 is then selected based on the nervediameter at the intended location for cuff placement. Nerve size may beassessed using reference size (e.g., forceps of know width), a caliper,or a flexible gauge that wraps around the nerve, for example. The cuff1350 is then opened and placed around the nerve. The strap 1356 on thecuff 1350 may be used to facilitate placement of the cuff 1350 aroundthe nerve. A curved forceps may be placed under the nerve to grasp thestrap 1356 and gently pull the cuff 1350 onto the nerve. The strap 1356is then placed through the loop (buckle) 1358 on the cuff 1350. The cuff1350 may be available in two sizes (small and large), and the small cuffmay have an indicator mark (not shown) on the strap 1356 that should bevisible after insertion through the loop 1358. If the indicator mark isnot visible, the small cuff may be too small and should be replaced witha large cuff. The surgeon then verifies that the cuff 1350 is notpulling or twisting the nerve, and that there is contact between theinside of the cuff 1350 and the nerve.

A test stimulation is then performed to confirm correct positioning ofthe cuff 1350 on the nerve. To conduct a test stimulation, the proximalend of STL 1300 is plugged into the INS 1100 and the programmer system2100 is used to initiate a test stimulation signal delivered from theINS 1100 to the nerve via the STL 1300. The test stimulation isperformed while observing, for example, tongue movement by direct visualobservation, airway caliber by nasal endoscopy, lateralfluoroscopy/cephalogram, etc. Correct placement of the cuff on the nervemay be confirmed by, for example, observing tongue protrusion, anincrease in retro-glossal airway caliber, an increase in retro-palatalairway caliber, an increase in stiffness of the anterior and/or lateralwalls of the retro-glossal airway with or without an increase in airwaycaliber, anterior movement with or without inferior movement of thehyoid bone, among others. Incorrect placement of the cuff on the nerveis indicated, for example, when the tongue is observed to retract(posterior movement), a decrease in retro-glossal airway caliber, adecrease in retro-palatal airway caliber, superior movement andparticularly unilateral superior movement of the hyoid bone, amongothers. If necessary, the cuff 1350 may be repositioned at a differentlocation along the length of the nerve to obtain the desired effect. Thecapture threshold and impedance values are recorded and the STL 1300 isdisconnected from the INS 1100. A fascial wrap is then sutured over thecuff on the superficial side of the nerve.

A strain relief loop (L) in the STL 1300 is then created by arrangingapproximately 6 cm of the STL sigmoid body 1370 in a C-shape inside asmall subcutaneous pocket formed via the neck incision (A) by bluntdissection superficially along the lateral surface of the digastricmuscle in a posterior direction.

A pocket for the INS 1100 is then created by making an incision (B) downto the pectoralis fascia up to 2 finger breadths below the rightclavicle. The INS 1100 is preferably implanted on the right side tominimize cardiac artifact during respiratory sensing. Blunt dissectioninferior to the incision is used to create a pocket large enough to holdthe INS 1100. The pocket should be inferior to the incision (B) suchthat the incision (B) does not reside over the INS 1100 when laterplaced in the pocket.

A tunnel is formed for the STL 1300 using the tunneler 3000 (sheath 3020and cap 3030 placed over grasper 3010) to tunnel along a path (C) fromthe infraclavicular INS pocket to the neck incision (A). As shown inFIG. 11C, the lead carrier 3100 is then placed on the most proximalelectrical contact of the STL proximal connector 1310. The cap 3030 isremoved from the sheath 3020 to expose the jaws 3014 of the grasper 3010and grab the lead carrier 3100. While holding the sheath 3020 in place,the grasper 3010 is pulled proximally to pull back the STL 1300 throughthe sheath 3020, taking care not to pull out the C-shaped strain reliefor disturb the cuff. If the C-shaped strain relief loop (L) is pulledout, it should be replaced into the small pocket. The grasper 3010 isreleased from the lead carrier 3100 and the lead carrier 3100 is removedfrom the STL 1300. The sheath 3020 is then removed from the body leavingthe STL 1300 in place. The neck incision (A) need not be closed at thistime, but rather may b e closed later in the procedure allowingconfirmation that the C-shaped strain relief remains in the smallpocket.

The right RSL 1200 is placed near the right costal margin by making twosmall incisions (D and E) as shown. The medial incision (D) may be madeapproximately 40% (+/−5%) of the distance from the midline to themidaxillary line, and approximately two finger breadths superior to thecostal margin. The lateral incision (E) may be made approximatelyhalfway between the medial incision (D) and the midaxillary line (i.e.,extending from the medial incision (D), approximately 30% (+/−5%) of thedistance from the midline to the midaxillary line), and approximately upto two finger breadths superior to the costal margin. Using the tunneler3000 (sheath 3020 and cap 3030 placed over grasper 3010), a tunnel (F)is formed from the medial incision (D) to the posterolateral incision(E). The lead carrier 3100 is then placed on the most proximalelectrical contact of the RSL 1200 proximal connector 1210. The cap 3100is then removed from the sheath 3020 to expose the jaws 3014 of thegrasper 3010 and grab the lead carrier 3100. While holding the sheath3020 in place, the grasper 3010 is pulled proximally to pull back theRSL 1200 through the sheath 3020. The grasper 3010 is released from thelead carrier 3100 and the lead carrier 3100 is removed from the RSL1200. The sheath 3020 is then removed from the body leaving the RSL 1200in place. Each suture tab 1270 is secured to the underlying tissue bydissecting down to the muscle fascia adjacent the anchor tabs 1270 onthe RSL 1200 and suturing each anchor tab 1270 to the muscle fascia.Permanent sutures are recommended to avoid movement of the RSL 1200before tissue encapsulation, and braided suture material is recommendedfor knot retention. The left RSL 1200 is then implanted along the leftcostal margin in the same manner as described above.

The right RSL 1200 is then tunneled to the pocket (B) for the INS 1100.Using the tunneler 3000 (sheath 3020 and cap 3030 placed over grasper3010), a tunnel (G) is formed from the infraclavicular pocket to themedial incision (D). The lead carrier 3100 is placed on the mostproximal electrical contact of the RSL 1200 proximal connector 1210. Thecap 3030 is then removed from the sheath 3020 to expose the jaws 3014 ofthe grasper 3010 and grab the lead carrier 3100. While holding thesheath 3020 in place, the grasper 3010 is pulled proximally to pull backthe RSL 1200 through the sheath 3020. The grasper 3010 is released fromthe lead carrier 3100 and the lead carrier 3100 is removed from the RSL1200. The sheath 3020 is then removed from the body leaving the RSL 1200in place. The left RSL 1200 is then tunneled to the pocket for the INS1100 in the same manner as described above.

The STL 1300 and RSLs 1200 are then connected to the INS 1100. Since oneSTL port is not used in this example, a port plug (small siliconecylinder) is inserted into header port STL-2. The RSLs 1200 are pluggedinto ports RSL-A and RSL-B, the STL 1200 is plugged into port STL-1 andthe set screws are tightened to 1 click using a torque wrench.

A closed loop test may be performed to confirm proper operation byobservation of tongue protrusion in concert with inspiration. The INS1100 and proximal portions of the leads 1200/1300 are then placed intothe infraclavicular pocket, looping the excess lead length beneath oraround the INS 1100. Care should be taken not to pull out the C-shapedstrain relief loop (L) in the STL sigmoid lead body 1370 whilemanipulating the INS 1100 into place. The INS 1100 is then sutured tounderlying fascia through both suture holes found in the header 1110 ofthe INS 1100. Permanent sutures are recommended for to avoid movement ofthe INS before tissue encapsulation, and braided suture material isrecommended for knot retention. Another system test may be performed atthis point. After confirming that the C-shaped strain relief loop (L) ispresent in small pocket at neck incision, the incisions may be irrigated(optionally with an antibiotic solution) and closed using conventionaltechniques. After a healing period of approximately one month, thepatient may undergo a sleep study to confirm proper operation of thesystem and to titrate therapy.

An alternative lead routing schematic is shown in FIG. 11D. In thisalternative embodiment, the left and right lateral incision sites E arelocated 80% of the distance from the midline to the mid-axillary line,up to two finger breadths above the rib costal margin. The medialincision sites D are then located a straight line distance of 9.5 cmmedial, up to two finger breadths above the rib costal margin.

Screening Methods

As schematically shown in FIG. 12, an external system may be used toconduct a stimulation screening session prior to full implantationwherein the genioglossus muscle (innervated by the hypoglossal nerve) isstimulated with fine wire electrodes (FWEs) 2860 inserted submentallywith a needle during an otherwise conventional sleep (PSG) studyutilizing PSG equipment 2800. The FWEs 2860 may be inserted into thegenioglossus under the guidance of ultrasound. Stimulation signals maybe delivered to the genioglossus muscle by connecting the FWE's 2860 toan external stimulator and switch box 2870. The external stimulator andswitch box 2870 may comprise the INS 1100, programmer head 2200 andprogrammer interface 2400 in a common housing, with the stimulationoutput of the INS 1100 connected to the FWEs 2860 and the sensing inputof the INS 1100 connected to skin surface electrodes 2890 forbio-impedance respiration measurement. A stimulation marker outputsignal 2872 from the external stimulator and switch box 2870 to the PSGequipment 2800 allows stimulation and/or respiration data to besynchronized and merged with PSG data in near real time. The externalstimulator and switch box 2870 may include a manually operated switcharray to select a single FWE or a combination of FWEs 2860 to deliver astimulation signal to the genioglossus muscle. With this arrangement,stimulation may be delivered via FWEs 2860 automatically triggered byinspiration measured via skin surface electrodes 2890 or manuallytriggered via activating a manual trigger switch 2880. The efficacy ofdelivering stimulus to the genioglossus muscle may be observed andmeasured using conventional PSG parameters. Efficacious results may beindicated by a significant reduction in apnea hypopnea index, anincrease in flow, a decrease in critical closing pressure, and/or anincrease in airway caliber, for example. Patients that respondadequately to stimulation during the trialing period (“responder”) mayreceive the implanted device. Perhaps more importantly, patients that donot adequately respond to stimulation during the trialing period(“non-responder”) would not receive the implanted device.

As schematically shown in FIG. 13, an external system may be used toconduct a respiration screening session prior to full implantationwherein skin surface electrodes are placed on the skin at or near thelocations that the respiration sensing electrodes and INS would beimplanted. Bio-impedance measurements may be taken during a sleep studyto determine if an adequate bio-impedance signal may be obtained. Inaddition, different locations for the skin surface electrodes may betested to determine the optimal locations for the respiration sensingelectrodes during implantation.

The stimulation trialing period and the respiration trialing period maybe combined into a single study, wherein skin surface bio-impedancemeasurements may be used to provide closed-loop feedback for stimulatingsynchronous with inspiration. Patients would then be categorized asresponders or non-responders depending on the outcome of the closed-loopstudy.

Titrating Methods

As described previously, after implantation and a healing period ofapproximately one month, the patient may undergo a sleep (PSG) study toconfirm proper operation of the system and to titrate therapy. Titrationmay utilize the set-up illustrated in FIG. 10, wherein the programmersystem 2100 interfaces with the PSG equipment 2800. Titration generallyinvolves (1) selecting an optimal respiratory sensing signal and (2)selecting optimal stimulation signal parameters (e.g., stimulationintensity, respiratory phase adjustment). After titration, therapyefficacy may be measured using standard PSG techniques. For example: arespiratory sensing vector may be selected based on signal strength andstability, reliability; the stimulation amplitude may be selected basedon maximum airflow; the phase adjustment may be selected based onstimulation alignment with inspiratory airflow; and therapy efficacy maybe evaluated based on elimination of indicia of sleep disorderedbreathing such as AHI.

Selecting an optimal respiratory sensing signal involves selecting thebest vector defined by two sets of electrodes on the RSL or one set ofelectrodes on the RSL and the housing of the INS. Selection may be basedon maximum signal strength, consistent correlation to inspiration, andmaximum signal stability/reliability across sleep stages, bodypositions, and disordered breathing events, for example. A stable signalhas a minimum probability of signal inversion. A reliable signal has aminimum probability of signal loss, and therefore may preferably have aminimum threshold of 0.2 to 0.5 Ohms peak-to-peak, for example. Theoptimal vector may be selected by incrementally scrolling through all ora preferred subset of possible vectors while sampling the respirationsignal and comparing the signal against themselves or predefinedthresholds. This scrolling technique may be performed manually (withinputs via the programmer system) or automatically (i.e., programmed).The sampling technique may also be performed manually (visualobservation using programmer system) or automatically (i.e.,programmed). For practical purposes, the respiration sensing vector maybe evaluated while the patient is awake by having the patient assumedifferent body positions while at resting respiration. Alternatively,the respiration sensing vector may be evaluated while the patient isasleep during different stages of sleep and during different sleepdisordered breathing events. The INS is capable of streaming out datafrom two or more sensing vectors which allows simultaneous comparison.This may be especially useful during titration (body position testingand during sleep study) to minimize chance that evaluation of a givenvector is biased by events unrelated to a given vector.

Selecting optimal stimulation signal parameters (e.g., pulse amplitude,pulse frequency, pulse width, duty cycle, phase adjust, etc.) tooptimize efficacy (e.g., as measured by apnea index, hypopnea index,respiratory disturbance index, apnea-hypopnea index, and otherobstructive sleep apnea efficacy measures) is preferably performed whilethe patient is sleeping.

The adjustable stimulation parameters include pulse frequency (range of20 to 50 Hz, nominal 40 Hz), pulse width (range of 30 to 215 μs, nominal90 μs), pulse amplitude (range of 0.4 to 5.0 mA, nominal 0.4 mA), dutycycle (range of 41% to 69%, nominal 50%), and phase adjust (range of−1.5 to +0.5 s, nominal −0.5 s). In general, during the stimulationtitration process, it is preferable to begin with the lowest settingsfor pulse width (30 μs) and amplitude (0.4 mA) at a nominal frequency(40 Hz). If stimulation produces pulsatile (vibrating) contractions, thefrequency may be increased to 50 Hz. The pulse width is incrementallyincreased to 60 μs, then to nominal (90 μs), keeping Amplitude at 0.4mA. With the pulse width set to 90 μs, amplitude may be iteratedaccording to the process described hereinafter. If maximum amplitude isreached and additional intensity is required, the pulse width may beincreased while reducing amplitude to minimum (0.4 mA). If maximum pulsewidth (215 μs) is reached and additional intensity is required,frequency may be increased while reducing the pulse width to 90 μs andthe amplitude to minimum (0.4 mA).

An initial step in titrating may involve defining a stimulationoperating window, preferably while the patient is awake, defined at itslower limit by a capture threshold and at its upper limit by a comfortthreshold. The capture threshold may be defined as the stimulation levelat which some indication of a potentially beneficial effect (e.g., grosstongue movement or stiffening) is observed. The comfort threshold may bedefined as the stimulation level at which the patient experiences anunacceptable sensation (e.g., pain) while awake or at which the patientpartially or completely arouses (e.g., lighter stage of sleep or awake)during sleep. Human subjects have been observed to tolerate (i.e., notarouse) higher stimulation intensities while asleep than they couldtolerate while awake. The operating window may be determined at thebeginning of the titration sleep study (e.g. during set-up when thepatient is awake) to help determine a lower limit or starting point forstimulation (capture threshold) and an upper limit or ending point forstimulation (comfort threshold), between which the stimulation level maybe adjusted (e.g., increased) until an efficacious level is found.

Using the programmer system 2100 to set the stimulation parameters, thestimulation level may be initially set at the lower limit or apercentage (e.g., 50%) of the upper limit, followed by a monitoringperiod where efficacy is measured using standard. PSG techniques. Afterthe initial monitoring period, the stimulation level may beincrementally increased, followed by another monitoring period. This maycontinue in a step-wise fashion up to the upper limit for stimulation oruntil no significant difference in measured efficacy is discernablebetween stimulation levels. If no significant difference in measuredefficacy is discernable between a lower and higher stimulation level,the lower level may be selected as the desired stimulation dose.

Because efficacy measures (e.g., apnea-hypopnea index) typically takehours to collect, it may be desirable to create a controlled,flow-limited condition and measure a surrogate parameter (e.g., airflow,critical closing pressure, etc.) in order to complete the step-wisetitration process in a reasonable amount of time (e.g., a single or halfnight sleep study). In addition, because a number of sleep conditions(e.g., sleep stage) change over the course of an all night study, it isbeneficial to titrate therapy over a shorter period of time during whichsleep conditions are less likely to change as significantly. To create aflow-limited state, the patient may be fitted with a CPAP (continuouspositive airway pressure) device comprising a blower connected via ahose to a mask (incorporating a airflow meter such as apneumotachometer) placed over the patient's nose and/or mouth. The CPAPdevice may have the capability to deliver variable pressure down toapproximately 0 cm H₂O or lower, in increments of 0.10 cm H₂O or less,for example. Such a CPAP device is also called a P device for itsability to assist in making critical closing pressure measurements ofthe upper airway using techniques developed by Schwartz et al. Theairway in people with obstructive sleep apnea will partially orcompletely occlude during sleep in the absence of adequate positiveairway pressure. Thus, adjusting the CPAP pressure below the therapeuticlevel for a given patient will create a controlled flow-limitedcondition. Using these techniques, the stimulation intensity level(e.g., current, mA) or other stimulation parameter (e.g., pulsefrequency, pulse duration, phase adjustment, etc.) may be titrated byprogressively creating greater flow restriction while determining if achange (e.g., an increase) in a stimulation parameter (e.g., intensity)results in an increase in flow.

With reference to FIGS. 14A and 14B, stimulation may be delivered atdifferent levels, different sequences, and different modes duringtitration. These stimulation alternatives may also be used for therapydelivery, if desired. In FIG. 14, each burst of stimulation is shown asa positive square wave and corresponds to a train of pulses as describedpreviously. The bottom trace #7 in FIGS. 14A and 14B correspond to arespiratory flow signal wherein the negative portion of the tracecorresponds to inspiration, and the positive portion of the tracecorresponds to expiration.

As shown in FIGS. 14A and 14B, stimulation bursts may be delivered atdifferent levels and in different sequences. For example, thestimulation burst may be programmed to be “A or B” (traces #1, #4 and#8), where stimulation is delivered at level “A” until commanded todeliver at level “B”, or delivered at level “B” until commanded todeliver at level “A”. Stimulation level “A” may correspond to a firstselected level and stimulation level “B” may correspond to a secondselected level, wherein the first level “A” is different than the secondlevel “B” in terms of amplitude, pulse width and/or duration.Alternatively, the stimulation burst may be programmed to be “nested”(traces #2 and #3), where the stimulation burst comprises a composite oflevels “A” and “B”. As a further alternative, the stimulation burst maybe programmed to “toggle” (traces #5 and #6) between the same ordifferent level in a repeating pattern (e.g., “AB”, “ABAB”, “0A0B”,“AA”, etc.).

Also as shown in FIG. 14, stimulation may be delivered in three basicmodes: manual synchronized; inspiratory synchronized; and triggered.Traces #1 and #2 illustrate manually synchronized stimulation delivery,wherein stimulation is delivered by manually entering a command via theprogrammer system to initiate stimulation delivery of each burst (e.g.,when the user observes or anticipates inspiration on PSG, the usermanually enters a command to initiate stimulation delivery). Traces #3,#4, #5 and #8 illustrate inspiratory synchronized stimulation delivery,wherein stimulation is automatically delivered according to an algorithmthat predicts the inspiratory phase and initiates stimulation deliveryat a desired time relative to inspiration such as at or just prior toinspiratory onset. Trace #6 illustrates triggered stimulation delivery,wherein each stimulation burst is initiated and terminated by a fiducialof the respiratory signal (e.g., positive peak, negative peak,cross-over point, etc.) which may or may not correspond to aphysiological event (e.g., inspiratory onset), and which may or may notincorporate a fixed delay. Thus, in triggered mode, the stimulationburst is initiated by a fiducial and terminated by the next occurrenceof the same fiducial in a repeating pattern.

The manually-synchronized A or B mode (trace #1) allows the user toprogram stimulation parameters for two (A & B) separately deliverablestimulation bursts. On user command, a single burst of stimulation isdelivered almost immediately corresponding to A's settings, likewise forB. A and B can be defined with unique amplitudes, pulse widths, anddurations; but with a common frequency. The dots on trace #1 indicatethe time of manual command followed by the delivery of stimulationimmediately thereafter.

The manually-synchronized nested burst (trace #2) allows the user toprogram stimulation parameters for a nested stimulation burst. On usercommand, a single burst of stimulation is delivered almost immediatelycorresponding to the nested burst parameters. The user defines thenested burst parameter by programming stimulation parameters for aprimary mode and separately for a secondary mode. The secondary mode isof shorter duration than the primary mode. The secondary mode may becentered on the primary mode as shown, or shifted to the beginning orend of the primary mode. The two modes can be defined with uniqueamplitudes, pulse widths, and durations; but with a common frequency.The dots on trace #2 indicate the time of command followed by thedelivery of stimulation immediately thereafter.

The inspiratory-synchronous nested mode (trace #3) delivers stimulationbursts synchronous with inspiration as determined by device and therapydelivery algorithm settings and sensed respiratory signal. This mode issimilar in function to manually-synchronous nested mode (trace #2) withthe following three differences: first, after user command thestimulation burst does not begin immediately but instead is deliveredduring the next inspiration as predicted by the therapy deliveryalgorithm; second, the duration of the stimulation burst is notprogrammed but is instead determined by the therapy delivery algorithm;and third, the nested stimulation burst will continue to be delivered onevery respiratory cycle until stopped. The lines below trace #3 indicatethe time window during which a command will cause therapy to begin onthe following inspiration.

The inspiratory-synchronous A or B mode (trace #4) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous nested mode (trace#3) except that the stimulation bursts comprise A or B as in themanually-synchronized A or B mode (trace #1). The selected (A or B)stimulation burst will continue to be delivered on every respiratorycycle until the other burst is selected or until stopped. The linesbelow trace #4 indicate the time window during which a command willcause therapy to begin or change on the following inspiration.

The inspiratory-synchronous ABAB mode (trace #8) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous nested mode (trace#4) except that the stimulation bursts alternate between A or B on eachburst. The stimulation bursts will continue to be delivered on everyrespiratory cycle until stopped. The lines below trace #8 indicate thetime window during which a command will cause therapy to begin or end onthe following inspiration.

The inspiratory-synchronous toggle mode (trace #5) also deliversstimulation bursts synchronous with inspiration as determined by deviceand therapy delivery algorithm settings and sensed respiratory signal.This mode is similar to the inspiratory-synchronous A or B mode (trace#4) except that the stimulation bursts are toggled. As shown, thetoggled stimulation burst sequence comprises 0A0B (i.e., no stimulation,stimulation level A, no stimulation, stimulation level B), whichcontinue to be delivered on each 4-breath series of respiratory cyclesuntil stopped.

The triggered toggle mode (trace #6) is similar in function to theinspiratory-synchronous toggle mode (trace #5) except that thestimulation burst sequence 0A0B is initiated and terminated by arecurring fiducial of the respiratory signal.

An example of a stimulation amplitude titration method is illustrated inFIG. 15A. In the illustration, three traces are shown: CPAP (pressure incm H₂O); STIM (stimulation amplitude in mA); and V_(i)max (maximuminspiratory nasal airflow in mL/min as measured by pneumotach or otherflow sensor). Initially, the stimulation amplitude is set to the capturethreshold, and the CPAP pressure is set to an efficacious level for agiven patient (typically above 5 cm H₂O and determined in a prior sleepstudy). In period “A”, the CPAP pressure is gradually decreased until aflow restricted state is reached in period “B” as detected by a drop inV_(i)max. In period “C”, the stimulation amplitude is increased whilethe CPAP pressure remains constant until an unrestricted flow state isreached in period “D” as detected by a rise in V_(i)max. In period “E”,the CPAP pressure is again gradually decreased until a flow restrictedstate is again reached in period “F” as detected by a drop in V_(i)max.In period “G”, the stimulation amplitude is again increased while theCPAP pressure remains constant until an unrestricted flow state isreached in period “H” as detected by a rise in V_(i)max. This iterativeprocess is repeated until the CPAP pressure reaches approximately 0 cmH₂O or until no further flow benefit is observed with increasingstimulation amplitude as shown in period “I”. The desired stimulationdose may be set to correspond to the lowest stimulation amplituderequired to mitigate restricted flow at a CPAP pressure of approximately0 cm H₂O or the lowest stimulation amplitude for which there is nofurther benefit in flow, whichever is lower. In addition, therapy can beadjusted to prevent flow restrictions at a nasal pressure slightly belowatmospheric to ensure efficacy under varying conditions that mayotherwise compromise airflow (e.g., head flexion, nasal congestion,etc.).

Another example of a stimulation amplitude titration method isillustrated in FIG. 15B. In addition to the stimulation amplitudetitration technique described above with reference to FIG. 15A,stimulation amplitude titration can be done through a different approachthat has two parts. The two parts are: with patient awake and withpatient asleep. These will henceforth be known as awake titration andsleep titration respectively. During awake titration, the stimulationamplitudes that cause the lowest level of muscle contraction, tonguedisplacement, and muscle contraction at the threshold of comfort arerecorded for the different frequency and pulse width settings.

This will be followed by a sleep titration, two examples of which areillustrated in FIGS. 15B and 15C. In FIGS. 15B and 15C, three traces areshown: CPAP (pressure in cm H2O); STIM (stimulation amplitude in mA);and CYCL (cyclic breathing associated with the patient's sleepdisordered breathing state). In addition, several points on the STIMtrace are indicated: ATHR (the arousal threshold, or the loweststimulation amplitude that causes arousal); CTHR (the capture threshold,or the lowest stimulation amplitude where muscle contraction iseffected). Traces not shown include those of respiratory flow and oxygensaturation level; although these variables are expected to be affectedby stimulation. An effect of stimulation on respiratory flow isdescribed with reference to FIG. 15A.

In FIG. 15B, sleep titration is carried out with the patient atatmospheric pressure and preferably in the supine position. However,this stimulation level titration is expected to be repeated throughoutthe sleep titration period with the patient in different conditions,including different body positions and sleep stages. After onset ofsleep, in region A, the patient is experiencing what to them would beconsidered severe sleep disordered breathing. Stimulation amplitude isalso periodically increased in region A. During these periodic increasesthe lowest stimulation amplitude that causes muscle contraction is alsoidentified. In region B, stimulation amplitude continues to beperiodically increased, which reduces the degree of but does not abolishthe sleep disordered breathing that the patient experiences. In region Cafter continued increase of the stimulation amplitude a level thatabolishes the sleep disordered breathing of the patient is achieved. Ifthis stimulation amplitude is reached in conditions considered to bemost challenging, then this stimulation level could be considered thetherapeutic level. In region D stimulation is turned OFF, which causesthe patient to go into sleep disordered breathing. In region E, thetherapeutic stimulation level is turned back ON and the patient's sleepdisordered breathing is abolished once again. In region F, continuedperiodic increase of stimulation amplitude leads to levels that causearousal. The arousal threshold is thus identified. In this titrationprocess, the stimulation level that abolishes the patient's sleepdisordered breathing without causing arousal and with the patient in themost challenging conditions is identified.

In FIG. 15C, sleep titration is started with the patient at atmosphericpressure. However, if a stimulation level that completely abolishessleep disordered breathing without causing arousal is not achieved, thensome sub-therapeutic CPAP (the patient's therapeutic CPAP will have beenidentified in a previous sleep study) could be used to complementstimulation for the delivery of therapy. After onset of sleep, in regionA, the patient is experiencing what to them would be considered severesleep disordered breathing. Stimulation amplitude is also periodicallyincreased in region A. During these periodic increases the loweststimulation amplitude that causes muscle contraction is also identified.In region B, stimulation amplitude continues to be periodicallyincreased, which reduces the degree of but does not abolish the sleepdisordered breathing that the patient experiences. In region C,continued periodic increase of stimulation amplitude leads to levelsthat cause arousal. The arousal threshold is thus identified. Note that,in this example, the stimulation level that causes arousal is reachedbefore the level that completely abolishes sleep disordered breathingcould be. In region D, a stimulation level that is just below thearousal threshold is maintained and the patient holds in moderate sleepdisordered breathing. In region E, a sub-therapeutic CPAP level thatabolishes the patient's disordered breathing is applied. This identifiesthe level of CPAP that complements stimulation in some patients. Inregion F, stimulation is either turned down or OFF from the level justbelow the arousal threshold, leading the patient to go into disorderedbreathing. In some cases, where the patients' sleep disordered breathingcannot be abolished by stimulation only, some CPAP pressure may be usedto complement stimulation. This could help increase the likelihood ofCPAP compliance of some patients since the CPAP pressure is reduced. Inaddition, it could help analyze how far patients are from beingcompletely treated by either stimulation or CPAP.

Another example of a stimulation amplitude titration method isillustrated in FIGS. 16A and 16B. This method may be carried out over aperiod of breaths (e.g., 4-10) or very slowly over several minutes(e.g., dozens of breaths to verify that optimal stimulation intensityhas been identified). In the illustration, four traces are shown: onetrace for CPAP pressure (designated by a solid diamond, pressure in cmH₂O); and three traces for V_(i)max (maximum inspiratory nasal airflowin mL/min as measured by pneumotach or other flow sensor) forstimulation amplitudes “0”, “A” and “B”. V_(i)max at stimulationamplitude “0” (designated by an open circle) corresponds to flow withstimulation off. V_(i)max at stimulation amplitude “A” (designated by anopen triangle) corresponds to flow with stimulation set to a value “A”,and V_(i)max at stimulation amplitude “B” (designated by an asterisk)corresponds to flow with stimulation set to a value “B”, where “A” isslightly less than “B”. Stimulation is delivered alternately at levels“A” and “B” with intermediate “0” levels (e.g., “0A0B”). Alternatively,stimulation may be delivered alternately at levels “A” and “B” withoutintermediate “0” levels (e.g., “AB”), which may be advantageous becausethe sequence may be executed faster and because arousal may otherwiseoccur due to low flow conditions at stimulation level “0”.

Initially, the CPAP pressure is set to an efficacious level for a givenpatient (typically above 5 cm H₂O and determined in a prior sleepstudy). With the stimulation amplitude set to “0” (i.e., stimulation isturned off), the CPAP pressure is gradually decreased while measuringV_(i)max to obtain a base-line reading when flow is un-restricted(beginning) and subsequently restricted. The stimulation amplitude isthen set to alternate between “A” and “B”, where “A” is set to thecapture threshold and “B” is set slightly higher than “B” (e.g., 0.1-1.0mA higher). The CPAP pressure is then gradually decreased (or droppedfor a short series of breaths and returned to baseline if needed tomaintain a passive state) while measuring V_(i)max to determine the flowat each stimulation level as shown in FIG. 16A. The values of “A” and“B” are incrementally increased and the CPAP pressure is again graduallydecreased while measuring flow. This iterative process is repeated untilthe traces converge as shown in FIG. 16B, demonstrating that no furtherbenefit in flow is realized with an increase in stimulation. The therapysetting may then be set to correspond to the lower stimulation amplitudevalue (“A”) where the traces for “A” and “B” converge. Note that FIGS.16A and 16B display the case where no arousal occurs during the gradualdecrease in CPAP pressure. In practice, it is expected that arousalswill occur before the process can be taken to complete conclusion asshown in the Figures. In the event of arousals, the iterative process isrepeated based upon convergence of the traces prior to the point ofarousal.

Another example of a stimulation amplitude titration method isillustrated in FIG. 17. FIG. 17 illustrates this method using astimulation sequence comprising “0A0B”, although a stimulation sequencecomprising “AB” may be used as an alternative. In FIGS. 17 and 18: “F”refers to peak inspiratory flow; “F.0” refers to flow with nostimulation; “F.A” refers to flow with stimulus intensity “A”; “F.B”refers to flow with stimulus intensity “B”; “OPEN” indicates that theairway is open, with no flow limitation; “Rx” indicates that the airwayis restricted (steady state flow limitation); “↑S.A” (or “↑S.B”)indicates that the intensity of stimulus “A” (or “B”) should beincreased; “↓P” indicates that CPAP (nasal) pressure should be reduced;“ΔS” is the difference between stimuli A and B; and “ΔS=max” is whenstimulus “B” is the maximum difference in intensity from stimulus “A”that will be tested (1.0 mA is recommended for this value).

Step 1 (holding pressure) in this method involves adjusting CPAP (nasal)pressure to the lowest holding pressure where maximum inspiratory flow(V_(i),max) is not limited, and recording various data. Step 2 (attainoscillation/steady state flow limitation) involves reducing CPAP (nasal)pressure until flow oscillation occurs, recording data, increasing CPAP(nasal) pressure until oscillations cease, thereby achievingsteady-state flow limitation (SSFL), and recording data. Step 3(activation threshold, defined as lowest stimulation intensity with ameasurable effect on flow) involves selecting triggered toggledstimulation mode 0A0B with stimulation amplitude level A=stimulationamplitude level B=0.4 mA, and pulse width=30 microseconds (if no effect<90 microseconds, increment to 90 microseconds). Then, with stimulationamplitude level A=B, both amplitude levels A and B are incrementallyincreased until flow differs between stimulated breaths (level=A=B) andnon-stimulated breaths (level=0). If necessary, CPAP (nasal) pressuremay be adjusted to ensure SSFL during non-stimulated breaths. Step 4(optimize stimulation level) involves selecting triggered toggledstimulation mode 0A0B with stimulation amplitude level A=activationthreshold (determined in step 3) and stimulation amplitude levelB=smallest increment greater than level A, and then executing thefollowing sub-routine:

(a) While there is a significant difference in Vi,max (>10%) betweenStim A and B, increase both A and B amplitudes by same amount (0.1mA-0.5 mA) until no significant difference in Vi,max is observed;

(b) If Stim A breaths not flow limited, reduce CPAP (nasal) pressureuntil flow limitation is achieved and return to step (a); else, continueto (c);

(c) If Max Delta Slim (difference between Slim A and Slim B=1.0 mA, forexample) is reached, decrement CPAP (nasal) pressure; else increase SlimB; continue to (d);

(d) Stop if either the lowest CPAP pressure level to be tested isreached (e.g., atmospheric or sub-atmospheric), or if maximumstimulation intensity of the INS is reached; else return to (a).

The therapy setting may then be set to correspond to the lowerstimulation amplitude value (“A” or “B”) where there is no increase inflow benefit. Optionally an additional margin may be added to thesetting (a fixed value or a percentage of the setting, e.g., 10% to 20%)to accommodate changing physiologic conditions.

FIG. 18A is a flow chart illustrating the method described withreference to FIG. 17. FIG. 18B provides a legend for the flow chart ofFIG. 18A.

From the foregoing, it will be apparent to those skilled in the art thatthe present invention provides, in exemplary non-limiting embodiments,devices and methods for nerve stimulation for OSA therapy. Further,those skilled in the art will recognize that the present invention maybe manifested in a variety of forms other than the specific embodimentsdescribed and contemplated herein. Accordingly, departures in form anddetail may be made without departing from the scope and spirit of thepresent invention as described in the appended claims.

What is claimed is:
 1. A programmable neurostimulator comprising: aprocessor configured to: deliver a respiratory therapy to a subject;titrate a stimulation setting of the respiratory therapy while thesubject is awake by delivering a first set of stimulation pulses at aplurality of first stimulation setting values between a lower limitdefined by a capture threshold corresponding to a beneficial effect ofthe respiratory therapy and an upper limit defined by a comfortthreshold corresponding to an unacceptable sensation experienced by thesubject; and subsequently, while the subject is asleep, repeat the stepof titrating the stimulation setting of the respiratory therapy bydelivering a second set of stimulation pulses at a plurality of secondstimulation setting values, wherein one or more of the plurality ofsecond stimulation setting values is different than one or more of theplurality of first stimulation setting values and the plurality ofsecond stimulation setting values are between the lower limit defined bythe capture threshold and a second upper limit defined by a threshold atwhich the subject is expected to at least partially arouse from sleep.2. The programmable neurostimulator of claim 1, wherein the processor isconfigured to repeat the step of titrating the stimulation setting ofthe respiratory therapy by further subsequently delivering a third setof stimulation pulses at a plurality of third stimulation settingvalues, wherein one or more of the plurality of third stimulationsetting values is different than one or more of the plurality of secondstimulation setting values.
 3. The programmable neurostimulator of claim2, wherein the processor is configured to repeat the step of titratingthe stimulation setting of the respiratory therapy by further comparingresponses of the subject to the second and third sets of stimulationpulses.
 4. The programmable neurostimulator of claim 3, wherein theprocessor is configured to compare the responses of the subject bycomparing air flow of the subject responsive to the second and thirdsets of stimulation pulses.
 5. The programmable neurostimulator of claim4, wherein the processor is further configured to deliver controlledpressure to an airway of the subject while performing at least one oftitrating or repeating the step of titrating the stimulation setting ofthe respiratory therapy.
 6. The programmable neurostimulator of claim 5,wherein the controlled pressure creates a flow-limited state.
 7. Theprogrammable neurostimulator of claim 2, wherein the processor isconfigured to deliver the second and third sets of stimulation pulses ina sequence to define a stimulation pattern.
 8. The programmableneurostimulator of claim 7, wherein the stimulation pattern comprises atleast one of a period of no stimulation, an AB pattern, an ABAB pattern,an 0A0B pattern, or an AA pattern.
 9. The programmable neurostimulatorof claim 7, wherein the processor is configured to deliver thestimulation pattern in at least one of a manual mode, a synchronizedmode, or a triggered mode.
 10. The programmable neurostimulator of claim2, wherein the third set of stimulation pulses comprises a differentamplitude than the second set of stimulation pulses.
 11. Theprogrammable neurostimulator of claim 1, wherein the processor isconfigured to titrate the stimulation of the respiratory therapy suchthat the titrating defines a stimulation level operating window having acapture stimulation level and a maximum comfort stimulation levelinclusively between which the programmable neurostimulator is configuredto deliver the first set of stimulation pulses; and wherein the capturestimulation level corresponds to respiratory muscle movement and themaximum comfort stimulation level is greater than the capturestimulation level.
 12. The programmable neurostimulator of claim 11,wherein the respiratory muscle movement is at least one of an initialresponse of the respiratory muscle to a stimulation, a tongue movement,or a tongue stiffening.
 13. The programmable neurostimulator of claim11, wherein the maximum comfort stimulation level corresponds to atleast one of a sensation of pain or an inability to sleep.
 14. Theprogrammable neurostimulator of claim 11, wherein the processor isconfigured to deliver the second set of stimulation pulses at amagnitude that is greater than the maximum comfort stimulation level.15. The programmable neurostimulator of claim 1, wherein the processoris configured to deliver the awake titration by performing at least oneof: determining a stimulation level operating window; determining astimulation level that causes muscle contraction; or determining astimulation level that causes subject discomfort.
 16. A programmableneurostimulator comprising: a processor configured to: deliver arespiratory therapy to a subject; identify a stimulation operatingwindow for the respiratory therapy, wherein the stimulation operatingwindow includes a first threshold and a second threshold, wherein thefirst threshold is defined as a first level of stimulation at which abeneficial response is observed in an upper airway of the subject, andwherein the second threshold is defined as a second level of stimulationgreater than the first level of stimulation; wherein the secondthreshold comprises an awake level at which the subject experiences anunacceptable sensation while awake and an asleep level greater than theawake level at which the subject is expected to at least partiallyarouse from sleep; and wherein the programmable neurostimulator isconfigured to identify the stimulation operating window for therespiratory therapy by: titrating a stimulation setting of therespiratory therapy while the subject is awake by delivering successivestimulation bursts until the first threshold and the awake level of thesecond threshold are identified, wherein at least one of the successivestimulation bursts includes an intensity different than another one ofthe successive stimulation bursts; and subsequently repeating the stepof titrating the stimulation setting of the respiratory therapy whilethe subject is asleep by delivering successive stimulation bursts untilthe asleep level of the second threshold is identified.
 17. Theprogrammable neurostimulator of claim 16, wherein the processor isfurther configured to deliver controlled pressure to an upper airway ofthe subject while performing at least one of titrating or repeating thestep of titrating the stimulation setting.
 18. The programmableneurostimulator of claim 17, wherein the controlled pressure creates aflow-limited state.
 19. The programmable neurostimulator of claim 16,wherein the beneficial response comprises a muscle contraction.
 20. Theprogrammable neurostimulator of claim 16, wherein the unacceptablesensation comprises at least one of pain, arousal from sleep, orinability to sleep.